Culture

Madrid, Spain, 14 June 2019: The results of a survey presented today at the Annual European Congress of Rheumatology (EULAR 2019) highlight the significant impact of rheumatic and musculoskeletal diseases (RMDs) on mental health and a worrying lack of psychological care.1

"Not enough is being done to identify mental health issues and provide the support needed to RMD patients," said Professor Thomas Dörner, Chairperson of the Scientific Programme Committee, EULAR. "This survey highlights the huge importance of pain on the psychological well-being of RMD patients and the critical need to improve the support on offer. These results should act as a wake-up call to services across Europe."

A survey of over 900 RMD patients revealed that pain had caused one in ten to have suicidal thoughts within the previous four weeks. Pain had also caused 58% to feel that everything was unmanageable for them.1

Another important finding was a reciprocal relationship between sleep and pain where 69% identified the quality of their sleep as having a negative influence on their pain. In return, two thirds of patients rarely or never feel fully rested when they wake up in the morning, with 36% taking painkillers to improve their sleep.1

"Our study indicates that pain and poor quality of sleep have a huge impact on a patient's daily life, especially on their mental health," said Lene Mandrup Thomsen, the Danish Rheumatism Association, Denmark. "We are using the results of this study in our political work to help campaign for better treatment and support for patients with chronic pain in our healthcare system."

Of the participants, 83% have pain daily or several times a week and 46% have received strong painkillers over the last year. Despite a strong focus from Danish authorities on reducing their prescription, less than a quarter of respondents had been offered an alternative to strong painkillers.1

The survey was created by the Danish Rheumatism Association and was completed by over 900 members of a user panel consisting of people who suffer from at least one RMD.1

Results of another survey, also presented today at EULAR 2019, support these findings by revealing a worrying lack of psychological care for patients with rheumatoid arthritis and adult juvenile idiopathic arthritis (AJIA) in the UK.

In this survey, a quarter of the 1,620 people with rheumatoid arthritis or AJIA were experiencing clinical levels of anxiety or depression. Over half of these had never received a formal diagnosis. However, most concerningly, half of the respondents with rheumatoid arthritis and a third of those with AJIA who had either clinical levels or a formal diagnosis of anxiety or depression had never received any psychological support.2

"Our results highlight that, despite guidelines, many patients in the UK are not receiving the psychological support they need," said Dr Hayley McBain, Health Psychologist, City, University of London, United Kingdom. "It is imperative for rheumatology services to routinely measure anxiety and depression in order to intervene before the individual is in crisis."

The survey was conducted by the National Rheumatoid Arthritis Society (NRAS) in the UK and was designed by patients and researchers. Participants were recruited via social media platforms, membership and non-membership lists and in newsletters and forums. Recruitment was focused on those diagnosed with rheumatoid arthritis or AJIA aged 18 years and over.2

Abstract number: OP0347-PARE/OP0318-HPR

Lead VITALE investigator Dr Marie Courbebaisse (Paris, France), commented: "Our study shows that currently recommended doses of vitamin D are not sufficient to protect patients from the risk of fracture after kidney transplantation. This challenges advice in the current international KDIGO guidelines, which recommend using low doses of cholecalciferol similar to those recommended for the general population."

Kidney transplant recipients are at increased risk of fracture due to a combination of factors. As the kidneys fail, they are no longer able to maintain normal levels of parathyroid hormone, vitamin D, and blood levels of calcium and phosphate, which are important for bone health. As a result, patients are likely to have renal bone disease--known as chronic kidney disease-mineral bone disease (CKD-MBD) at the time of their transplant; or they may develop the condition if their transplanted kidney has suboptimal function. Some immunosuppressant drugs, given to prevent organ rejection, also have adverse effects on bone health. Current guidelines recommend correction of vitamin D deficiency or insufficiency to help improve bone health, based on guidelines in the general population [2]. However, high-grade evidence to support this recommendation has been lacking [3].

Vitamin D? (cholecalciferol) is the form of vitamin D that is naturally made by the body through exposure to direct sunlight. The aim of the VITALE study was to compare the transplantation. A prospective, multicenter, double-blind, controlled trial, VITALE randomly assigned 536 kidney transplant recipients (mean age 50.8 years, 335 males) to either 100,000 IU (high dose) or 12,000 IU (low dose) cholecalciferol every two weeks for two months, then monthly for 22 months. In the study, 'low dose' corresponded to a minimum recommended intake of 400 UI/day.

After 24 months, vitamin D levels were significantly greater in the high-dose group compared to the low-dose group: 43.1(12.8) ng/mL versus 25.1(7.4) ng/mL compared with 20.2(8.1) versus 19.2(7.0) ng/mL at study inclusion (p

Professor Carmine Zoccali, ERA-EDTA President concluded: "The VITALE study is important for nephrologists and their patients, because it shows that high-dose vitamin D is an effective way of lowering the rate of fractures after kidney transplantation, with a very low risk of any side effects. More broadly, we see yet again that other benefits for vitamin D seen in observational studies are not reflected when supplementation is tested in randomized controlled trials."

WHAT:
National Institutes of Health scientists have used human skin cells to create what they believe is the first cerebral organoid system, or "mini-brain," for studying sporadic Creutzfeldt-Jakob disease (CJD). CJD is a fatal neurodegenerative brain disease of humans believed to be caused by infectious prion protein. It affects about 1 in 1 million people. The researchers, from NIH's National Institute of Allergy and Infectious Diseases (NIAID), hope the human organoid model will enable them to evaluate potential therapeutics for CJD and provide greater detail about human prion disease subtypes than the rodent and nonhuman primate models currently in use.

Human cerebral organoids are small balls of human brain cells ranging in size from a poppy seed to a small pea. Their organization, structure, and electrical signaling are similar to brain tissue. Because these cerebral organoids can survive in a controlled environment for months, nervous system diseases can be studied over time. Cerebral organoids have been used as models to study Zika virus infection, Alzheimer's disease, and Down syndrome.

In a new study published in Acta Neuropathologica Communications, scientists at NIAID's Rocky Mountain Laboratories discovered how to infect five-month-old cerebral organoids with prions using samples from two patients who died of two different CJD subtypes, MV1 and MV2. Infection took about one month to confirm, and the scientists monitored the organoids for changes in health indicators, such as metabolism, for more than six months. By the end of the study, the scientists observed that seeding activity, an indication of infectious prion propagation, was present in all organoids exposed to the CJD samples. However, seeding was greater in organoids infected with the MV2 sample than the MV1 sample. They also reported that the MV1-infected organoids showed more damage than the MV2-infected organoids.

The scientists also noted other differences between how the MV1 and MV2 infections evolved in the organoids. They plan to further investigate those differences in hopes of identifying how different subtypes of CJD affect brain cells. Ultimately, they hope to learn how to prevent cell damage and to restore the function of cells damaged by prion infection. The new system also provides opportunities to test potential therapeutics for CJD in a tissue model that mimics the human brain.

A team of scientists from the University of Granada (UGR), the Biohealth Research Institute in Granada (ibs.GRANADA), the city's San Cecilio Clinical Hospital, and the Centre for Biomedical Research in Epidemiology and Public Health (CIBERESP) has found that 9 out of 10 pairs of socks for babies and children from 0-4 years old contain traces of bisphenol A and parabens. The hormonal activities of these two endocrine disruptors have been linked to dysfunctions that can trigger illnesses in both children and adults.

This scientific study--the first of its kind to be conducted in Europe--reveals that fabrics can be a source of exposure to endocrine-disrupting chemical pollutants. This is of particular concern in the case of exposure among very young children.

The researchers also discovered major differences in the amount of the toxic product detected, depending on the type of outlet selling the socks. Samples of 32 pairs of children's socks (from new-borns to aged 48 months) were analysed, having been purchased in three different types of retail outlet, classified according to the price range of their products. The three types were: local bargain retailer (three pairs for €1.50-€1.80); low-cost, fast-fashion international retailer (three pairs for €3.00-€4.50); and a higher-quality international retail clothing brand (three pairs for €6.95-€7.95).

By using sophisticated analytical chemistry techniques and performing complex biological tests to quantify hormonal activity, the Granada-based researchers studied the presence of the plastic component bisphenol A, the preservatives known as parabens, and the hormonal activity (estrogenicity and androgenicity) of the sock extracts.

Local bargain retailer

The concentrations of the two chemicals found in the socks sold at the local bargain store in the sample reached a maximum of 3,736 ng of bisphenol A per gram of fabric. This average amount of bisphenol A was more than 25 times higher than that found in the socks sold by the low-cost international retailer and the higher-quality international brand. Parabens were found in all the products studied--in particular ethylparaben, followed by methylparaben--but in average concentrations lower than those of bisphenol A and with less pronounced differences between store type.

As was to be expected, given their high bisphenol A content and the presence of parabens, two out of every ten pairs of socks bought at the bargain retailer presented oestrogenic  hormonal activity; and one out of every three pairs bought at the same outlet presented anti-androgenic activity in the biological tests conducted. That is to say, the extracts taken from these items of clothing behaved like the female hormone and they antagonised male hormones. Due to this hormonal activity, bisphenols and parabens are endocrine disruptors associated with certain dysfunctions that can lead to illnesses in both children and adults. The spectrum of illnesses associated with exposure to endocrine disruptors is far-reaching, ranging from attention deficits and hyperactivity, to genitourinary disorders, premature secondary sexual development, and obesity in children. Among adults, they are linked to hypothyroidism, infertility, diabetes, and hormone-dependent cancers, such as breast cancer.

Using complex algorithms, the researchers also estimated the risk to babies and children of exposure, via the skin, to each of the chemical compounds. The interpretation is not straightforward, as little is known about how, and to what extent, they can be absorbed by the skin, or how much may be released during washing (and, in turn, the possible contamination of the water and thus the other baby items being washed). However, the researchers' main issue of concern is the possible exposure to these chemical compounds contained in clothing via the digestive tract, given how common it is for babies suck their own feet and socks. To address this, the research group has added a further slogan to its public awareness-raising campaign against exposure to endocrine disrupters, in particular alerting parents of small children: "Socks suck!"

Information campaign

The UGR research group is aiming to inform parents, train physicians and health workers to give timely recommendations, warn manufacturers and importers about the quality of their products, and make national and European governments aware of the problem, to urge them to take action on the issue. For example, governments need to enforce stricter regulation of endocrine disruptors in textiles--a facet of industrial and commercial activity that is currently overlooked.

Like Heracles' wife

The Deianiraeaceae, which has become the fourth family in the order Rickettsiales, currently contains one genus, Deianiraea. All previously investigated Rickettsiales are obligate intracellular specialised parasites. By contrast, Deianiraea not only attacks the victim from the outside, but also it never enters the host cell throughout its entire life cycle. Deianiraea colonises the extracellular surface of the ciliate Paramecium: the predatory bacterium attacks the ciliate and replicates on its surface, taking the victim's resources, and eventually its life.

The name for the newly discovered bacterium - Deianiraea - refers to the myth of Deianira, the wife of Heracles. According to legend, the centaur Nessus attempted to kidnap Deianira, but she was rescued by Heracles. Heracles shot the centaur with an arrow dipped in the Lernaean Hydra's venomous blood. The dying Nessus, seeking vengeance, persuaded Deianira to take some of his blood, as it would allegedly make a powerful love potion. When Deianira heard that Heracles had fallen in love with another woman, she feared that he would leave her. Deianira sent him a tunic smeared with the centaur's blood. The tunic poisoned with the Hydra's venom in the centaur's blood killed Heracles. 'Similarly, the Deianiraea bacterium kills the ciliates, covering the host cell like a poisoned tunic,' notes Alexey Potekhin, Professor at the Department of Microbiology of St Petersburg University and a member of the international research team.

Predator of the microworld

The novel bacterium was discovered by chance. Natalia Lebedeva is one of the co-authors of the study and a leading expert of the Centre for Culture Collection of Microorganisms at the St Petersburg University Research Park. She took a sample of water from a waste water stream in Larnaca, Cyprus. Microbiological analysis of the water sample revealed that it contained a large number of ciliates. Laboratory observation showed massive loss of cilia, which are employed for locomotion and feeding. This resulted in the death of the affected ciliate. Other paramecia, which were added into the same culture, also soon died. Upon closer inspection of the affected ciliates it became evident that the deciliated areas of the cell surface were covered by tightly packed bacteria - unknown to science at that moment.

'New bacterial families are rarely discovered these days. It is always an important finding, no matter what order this family may belong to. In our case, a new family has been found in a very well-studied order - the Rickettsiales. Previously, only DNA of related bacteria were detected in the samples. Therefore, the bacteria were classified as Rickettsia-like, as the scientists were not able to place them into the existing system of families of the order. It was the first time that we had found these bacteria alive. The molecular phylogenetic analysis enabled us to reassemble all the data fragments and, consequently, to establish a new bacterial family - Deianiraeaceae. One may say we were lucky,' says Alexey Potekhin.

Strong and almost independent

Unlike other Rickettsia-like bacteria, Deianiraea is not only able to replicate - to reproduce outside the cell - but also to sustain itself with less dependence on the host. 'Deianiraea possesses a higher capability to synthesise amino acids, compared to all other Rickettsiales. It can synthesise 16 amino acids, including the 8 that other representatives of the order cannot produce. 16 out of the 20 main amino acids is almost a full set. The rest it is most likely to acquire from its victims, but we do not know that for certain. Moreover, Deianiraea can synthesise nucleotides: other Rickettsiales do not do this because they receive them from the host,' Alexey Potekhin explains.

Another feature of Deianiraea is that it has several secretion systems. In bacteria, this enables protein secretion that can be employed for interaction with other cells as well. Deianiraea does have a specialised secretion system for interacting with other bacteria. It also has a specialised type IV secretion system which putatively enables it to establish contact with the ciliate. At present, the researchers have not yet established the exact mechanism of the parasite-host cell interaction, and what the bacterium may acquire from the ciliate or other host organisms.

Related to mitochondria

The order Rickettsiales encompasses three previously known families of highly diverse representatives of intracellular symbionts and parasites associated with eukaryotes, including animal and human pathogens (e.g., typhus). It has been suggested that all Rickettsia-like may have shared a common ancestor with mitochondria. Mitochondria in are responsible for ATP synthesis in all eukaryotic cells, i.e. for energy metabolism. The discovery of a novel -- extracellular -- Rickettsiales bacterium suggests that the evolutionary path of mitochondria may have been different, contrary to what has been previously assumed.

'Evolution, whenever possible, tends to choose the path of least effort, reducing the number of redundant functions: all that is unnecessary is eliminated. It has been assumed that the common ancestor of all Rickettsia-like bacteria was a specialised intracellular parasite with a low biosynthetic potential. In other words, it was unable to synthesise many of the essential substances, acquiring them from the host. It could sustain itself and reproduce only inside host cells. The results of our research allow us to assert with confidence that the last common ancestor of all Rickettsia-like bacteria led an extracellular lifestyle, lived in water, had a flagellum and was metabolically independent. It also must have had cellular systems that enabled parasite-host interactions. Adaptation to the lifestyle of intracellular parasites of the modern families of the Rickettsiales order would have evolved later in parallel and independently in different sub-lineages. The discovery of Deianiraea impels us to reopen the debate about the time when the ancestor of mitochondria would have established itself inside a proto-eukaryote, and the particular traits this mitochondrial ancestor would have possessed,' the scientist concludes.

A study out of Indiana and Purdue Universities sought to gain a better understanding, from the perspective of farmers, of the challenges and advantageous opportunities associated with using high tunnels for specialty crops in Indiana.

Analena Bruce (Indiana University), Elizabeth Maynard (Purdue University), and James Farmer (Indiana University) researched the application of this season-expanding growing technique in order to provide an in-depth understanding of farm-level challenges associated with high tunnel adoption and usage. Their results are detailed in the article, "Farmers' Perspectives on Challenges and Opportunities Associated with Using High Tunnels for Specialty Crops," published in HortTechnology.

High tunnels are essentially unheated greenhouses that can help farmers extend the growing season so that they can improve profitability and productivity of their farms. They provide protection from extreme weather such as high winds, heavy rain, hail, snow and drought.

Unlike greenhouses, high tunnels are simple structures over bare ground and its natural soil. They function without elaborate heating or cooling systems and are generally basic frames set into the ground and covered with one or two layers of greenhouse-grade plastic.

High tunnels are an increasingly popular part of the infrastructure among small and diversified farms that market their products directly to consumers. In addition to extending the growing season, research has strongly indicated that high tunnels can increase yield, enhance shelf life, and improve the quality of crops grown.

Initial observations into the use of high tunnels revealed that the additional labor and time requirements of high tunnel production, the increased complexity of transforming farming habits to high tunnel usage, soil fertility and management considerations, disease management, and limited winter markets all comprise the greatest challenges facing farmers adopting this technique.

The ability to differentiate their products based on higher quality and longer shelf life, the ability to obtain a premium price, the ability to maintain a source of income during the off-season, and the ability to produce complementary crops have been revealed as the most attractive advantageous opportunities for using high tunnels in farming.

The global production of specialty crops, such as high-value vegetables, has been transformed by the use of high tunnels to temper the effects of extreme weather events and climate conditions, and allow for extended growing seasons.

This study presents findings from qualitative research that was designed as a follow-up to a survey of farmers using high tunnels across Indiana. A qualitative approach was ideal for this study because it provided a richer picture of farmers' experiences with high tunnels and a better understanding of the specific challenges and opportunities alluded to earlier.

One of the more commonly mentioned challenges described by participating farmers was the added difficulty with keeping up with the time and labor required to manage their high tunnels. The researchers determined that one reason why high tunnel crops are more labor-intensive for farmers is because high tunnel planting and harvesting schedules are substantially different from what farmers are familiar with and require schedules that are separate from those of their vegetable crops growing in the uncovered portions of their fields.

The article showcases in-depth interviews for this effort that allow for the reporting of specific examples that illustrate the experiences of farmers with high tunnels. These specific examples prove to be very valuable for developing an understanding of the issues and how they can be addressed in the best way. Furthermore, these examples combined with the results of surveys and quantitative research will enable more rapid improvements in high tunnel production systems through research, improvements in technology, and education.

Developmental disorders are neurologically-based conditions that affect the acquisition of specific skills such as attention, memory, language and social interaction. Although they have a genetic cause, this is often difficult to detect through standard genetic analysis of the parents. The mutation found in the affected child is therefore termed a 'de novo' mutation (DNM).

« Although many new developmental disorders have been identified in recent years, there are many more to be discovered. Identifying them means that we will be able to give an accurate diagnosis to more patients and therefore allow them to have appropriate treatment and care, » Ms Joanna Kaplanis, a PhD student at the Wellcome Sanger Institute, Hinxton, UK, will tell the annual conference of the European Society of Human Genetics today (Saturday).

In the largest study to date on developmental delay, the researchers analysed genomic data from over 31,000 parent-child trios obtained from the UK's Deciphering Developmental Disorders Project, GeneDx, a US-based genetic testing company, and Radboud University Medical Centre in The Netherlands. Analysis of these trios yielded more than 45,000 DNMs. They developed an improved method to test for the enrichment (over-representation) of damaging DNMs in individual genes. « We found 307 significantly enriched genes, 49 of which are novel. With all of these genes we were able to explain about 51% of the DNM burden in our dataset. We then modelled different underlying genetic scenarios to get an idea of where the remaining de novo burden lies and how we can go about finding it," says Ms Kaplanis.

About 40% of developmental disorders are caused by DNMs, equivalent to about one birth in every 295 in the UK alone. The prevalence increases with the age of the parents. The disorders usually become apparent during childhood and include such conditions as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), intellectual disability, and Rett syndrome. They may be mild, but in many cases they are severe, and those affected will need lifetime support. However, when they are unidentifiable making a decision on the best care for the affected child is difficult.

Given the size of the dataset, the researchers were not surprised to have been able to identify new genes. « However, we were expecting to be able to explain more of the DNM burden than we did. This means that half of the DNM burden in patients with developmental disorders still remains unexplained, » says Ms Kaplanis. « This fact alone gives us clues about where the remaining burden lies and why we do not yet have the capacity to discover the remaining genes. »

A possible explanation is that the DNMs in the genes as yet undiscovered are less penetrant, i.e. they present symptoms in fewer people. « We may need to adapt our system of gene discovery in order to capture these less penetrant genes, » says Ms Kaplanis. « Incorporating more data from healthy populations may help to try and build a better picture of what they might be. «

The researchers also hope to increase their sample size in order to try to detect ever more genes associated with developmental disorders. However, the identification of 40 new genes already provides valuable information to clinicians and to drug developers. « Returning a genetic diagnosis is important when deciding on the best treatment and care for an individual, as well as providing new drug targets in rare diseases," Ms Kaplanis will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: "Developmental delay is often caused by new mutations arising during the formation of sperm or eggs. By combining data on new mutations identified in the DNA of more than 30.000 patients, the scientists could implicate a role for 49 new genes in developmental delay. This study shows the power of large-scale international collaboration to advance our understanding of this disorder and improve diagnostics as well as patient management."

A study out of Clemson University has demonstrated that inexpensive, easy-to-use temperature controllers are able to provide reliable set temperatures for the detailed observation of developmental rates in response to different temperature treatments.

Researchers Douglas Bielenberg and Ksenija Gasic engaged a methodical examination of the practical applications of these temperature control devises on cut stems, buds, and seeds.

The results of their study are detailed in the article, "Controlled-temperature Treatments with Low-cost Off-the-shelf Equipment for Bud or Seed Forcing Experiments," published in HortScience.

Inexpensive plug-and-play temperature controllers have recently become available. These allow a chest freezer to be programmed easily to hold a desired set point across a range of biologically relevant temperatures. Installation can be completed in a few minutes using consumer-grade chest freezers.

Characterizing the regulation of plant and seed development by temperature requires controlled exposure of replicate plants (whole or in part) to multiple temperature environments simultaneously. Experiments with seeds or other small plant segments can be performed on a thermal gradient table, which can generate many temperatures at once.

However, experiments involving larger plant parts, such as cut stems, require temperature control of a larger three-dimensional volume, such as an environmental chamber. Inexpensive access to the number of environmental chambers required for this sort of scientific observation is not easily available and can therefore limit the scope of experiments.

However, newly available plug-and-play temperature controllers allow conversion of a standard chest freezer into a controlled-environment chamber in minutes, with no custom modification.

To test the equipment, the researchers subjected an array of identical plant types and seeds to a variety of precise temperatures within an array of identical box freezers (chambers). They tested each chamber's temperature controller, recording internal temperatures at 10-minute intervals, to ensure the integrity of the equipment and the consistency of its output to maintain an exact and controlled environment during a 48-hour period, during which the chambers were not opened.

The effectiveness of the chambers on the effects of temperature on developmental rates was assessed with two biological assays: budbreak progress of peach floral buds warm-forced at different temperatures, and sunflower seed germination. Both budbreak and germination showed a clear temperature-dependent effect on development, with each decrease in temperature slowing development form the previous temperatures.

Understanding the minimum temperature for development is an important realm of knowledge for modeling plant phenology. The relationship between development rate and suboptimal temperatures can be used easily to calculate an estimated base temperature for optimal growth.

These newer inexpensive temperature-controllers will allow horticulturists, agronomists, foresters, and educators to design and perform experiments when multiple controlled-temperature environments are required without access to specialized facilities or skills. Off-the-shelf, easy-to-use components offer the potential to expand greatly the community of researchers who are able to incorporate temperature physiology into their investigations of plant development and phenology, particularly workers outside of traditional research institutions.

Madrid, Spain, 13 June 2019: The results of a study presented today at the Annual European Congress of Rheumatology (EULAR 2019), jointly organised with the Paediatric Rheumatology Society (PReS), demonstrate no vaccine infections, and no disease flare, in the 234 rheumatic patients who received live-attenuated booster vaccination while taking immune suppressing therapies.1

There are estimated to be over 75,000 children living with rheumatic diseases in Europe. Safe and effective vaccination is crucial given their increased risk of infections, however, in patients who are on high doses of therapies that supress the immune system, it is currently recommended to withhold live-attenuated vaccines (although this can be considered on a case-to-case basis). This is due to a theoretical, but not proven, risk of developing the infection. Live-attenuated vaccines contain viruses or bacteria that have been weakened, but not destroyed, in a laboratory. They cannot cause disease in healthy people but can still produce a strong immune response.

Some doctors already vaccinate their patients with rheumatic disease on immune supressing therapies with the live-attenuated MMR (measles, mumps, rubella) or MMRV (MMR, varicella) booster. This is because, in light of recent measles epidemics in Europe and in the US, they feel the theoretical risk of vaccination is much lower than the risk of disease. This study identified 234 such patients from 13 centres across 10 countries and found no vaccine infections and low rates of adverse events.1

"Patients with rheumatic and musculoskeletal diseases have an increased risk of infection and so it is vital to vaccinate where possible to save lives," said Professor Hans Bijlsma, President, EULAR. "There is a lot of 'fake news' surrounding vaccination in the media and online and therefore we welcome these data presented today which should help dispel some of the public worries."

In the study presented today, the live-attenuated MMR or MMRV booster vaccine was given to 110 cases on methotrexate with three reporting mild injection-site reactions, 76 cases on methotrexate plus anti-tumour necrosis factor (anti-TNF) with seven reporting mild transient AEs; and 39 cases on anti-TNF alone with one reporting fever. Other biologic therapies were used on the remaining patients, three were on tocilizumab, seven on anakinra, and five on canakinumab. The mean age of patients in the study was five years, 70% of patients were girls. The vast majority had juvenile idiopathic arthritis (n=206) with disease activity considered low, moderate and high in 38%, 7% and 2% respectively.1

"The positive results of our study suggest live-attenuated MMR and MMRV booster vaccination is safe in children with rheumatic diseases," said Prof. Yosef Uziel, pediatric department, Meir Medical Center, Sackler School of Medicine, Tel Aviv University, and PreS working party on vaccination, Israel. "Current recommendations are cautious due to low levels of evidence and so we are launching a prospective study on safety and efficacy of MMR booster vaccine in paediatric rheumatology patients treated with immunosuppressive therapy, including biological therapy."

The flu vaccine is not live-attenuated and is recommended in all patients affected by rheumatoid arthritis, regardless of treatment. However, there is data showing that patients are not being vaccinated as recommended and hence putting themselves at risk.

The first real-world study of the flu vaccine in patients with autoimmune rheumatic diseases (AIRDs) was presented today at EULAR 2019. The study included 14,928 AIRD cases and found no association between the flu vaccine and disease activity, prescription of corticosteroid, or vasculitis. In fact, results demonstrate the flu vaccine is associated with a significant reduction in fatigue in the 2-3 months post vaccination, and a significant reduction in primary-care consultations for joint pain in the three months post-vaccination period.6

"Our results clearly support the use of the flu vaccine in rheumatic patients and should dispel any fears people have about reported links to disease activity or vasculitis," said Dr. Georgina Nakafero, Academic Rheumatology, University of Nottingham.

Another reason cited for not vaccinating against flu in patients with rheumatic diseases taking immune suppressing therapies is that, because the body has a weakened immune system, the response to the vaccine may not be big enough to protect the patient from a subsequent flu infection.

A third study, also presented today during EULAR 2019, reveals that, in order to prevent one case of flu, you only need to vaccinate 10 people with rheumatoid arthritis on a tumour necrosis factor inhibitor whereas you need to vaccinate 71 healthy individuals. This is because, although the immunity developed in response to the vaccine may not be as strong in these patients, their increased risk of infection means more cases are prevented.7

"Our analysis provides further evidence on the effectiveness of flu vaccination in patients affected by rheumatoid arthritis receiving treatment with tumour necrosis factor inhibitors and should represent a call-to-action for all rheumatologists to consider vaccination in such patients," said Dr. Giovanni Adami, University of Verona, Rheumatology Unit.

Abstract numbers: OP0205, OP0267, and OP0230

BEER-SHEVA, Israel...June 13, 2019 - A research team led by Ben-Gurion University of the Negev (BGU) Prof. Iris Shai has published a significant long-term study on the impact of Mediterranean and low-carb diets and exercise, measuring their impact with magnetic resonance imaging (MRI) technology to map body fat.

In the study, "The Beneficial Effects of Mediterranean Diet Over Low-fat Diet May Be Mediated by Decreasing Hepatic Fat Content," published in the Journal of Hepatology, researchers conducted full-body MRI scans of 278 obese subjects, mapping their fat deposits before, during and after the 18-month trial period to analyze the effects of various diet regimes on body fat distribution.

The CENTRAL trial is a randomized, controlled trial conducted at BGU in collaboration with the Dimona Nuclear Research Center and Soroka University Medical Center in Israel, as well as Harvard University and Leipzig University in Germany.

The study showed that a low-carb Mediterranean diet had a greater effect on reducing fat around the liver, heart and the pancreas, compared to low-fat diets with similar calorie counts, although the weight loss was similar. The team also found that moderate physical exercise reduced the amount of visceral fat stored around the stomach.

The researchers reported that the dramatic 30% reduction in liver fat combined with moderate weight loss is a key element in reducing health risks associated with obesity over the long term. High hepatic fat content is associated with metabolic syndrome, type 2 diabetes mellitus and coronary heart disease. Together with moderate weight loss, fat around the heart decreased by 11% (about 70 cc reduction in volume) and visceral fat was reduced by 25%. Pancreatic and muscle fat was reduced by only 1 to 2%.

"Reduction in liver fat is a better predictor of long-term health than reduction of visceral fat, which was previously believed to be the main predictor," according to Prof. Shai, a member of BGU's S. Daniel Abraham International Center for Health and Nutrition and School of Public Health. "The findings are a significant contributor to the emerging understanding that for many obese individuals, excess liver fat is not merely a sign of health risks associated with obesity, including cardiovascular disease and diabetes, but is likely also a cause."

The research team tested the significance of reducing liver fat (in contrast to visceral fat) by comparing the results of some 278 overweight people who followed two reduced-calorie diet regimes: a Mediterranean diet and a low-fat diet. Following the subjects for 18 months demonstrated that changing their respective nutrition habits was consistent with the trial groups to which they were randomly assigned.

"Healthy nutrition, while also maintaining consistent, moderate weight loss, has a much more dramatic impact on levels of body fat related to diabetes, heart disease and cardiovascular disease than we previously thought," Prof. Shai says.

The CENTRAL study has achieved significant breakthroughs toward developing personalized nutritional protocols to address a variety of specific fat deposits using MRI technology, the most precise method currently available for mapping and quantifying fat deposits throughout the human body and for understanding their significance and the role they play.

The CENTRAL study, unprecedented in both its length and breadth, contributes a vast database, consisting of thousands of body images, for finding and mapping fat deposits in the human body. During a person's lifetime, fat cells move between body parts and that fat plays a variety of health roles, from defense to neutral to poisonous. By following the extent and breadth of these changes over time, the researchers, who have developed technologies to quantify specific types of fats, have now paved the way for deeper, more precise understanding of the dynamics of weight loss during a diet period.

The CENTRAL MRI Research Group includes: Ilan Shelef, Oded Komy, Noa Cohen, Dan Schwarzfuchs, Nitzan Bril, Michal Rein, Dana Serfaty, Shira Kenigsbuch, Hila Zelicha, Anat Yaskolka Meir, Lilac Tene, Avital Bilitzky, Gal Tsaban, Yoash Chassidim, Benjamin Sarusy, Uta Ceglarek, Joachim Thiery, Michael Stumvoll, Matthias Blüher, Meir Stampfer, Assaf Rudich and Iris Shai.

BOSTON (June 13, 2019)--Low levels of circulating vitamin K are linked to increased risk of mobility limitation and disability in older adults, identifying a new factor to consider for maintaining mobility and independence in older age, according to a study led by researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.

The study, published online in May in advance of print in the Journal of Gerontology: Medical Sciences, is the first to evaluate the association between biomarkers of vitamin K status and the onset of mobility limitation and disability in older adults.

"Because of our growing population of older people, it's important for us to understand the variety of risk factors for mobility disability," said Kyla Shea, first and corresponding author and a nutrition scientist in the Vitamin K Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University.

"Low vitamin K status has been associated with the onset of chronic diseases that lead to disability, but the work to understand this connection is in its infancy. Here, we're building on previous studies that found that low levels of circulating vitamin K are associated with slower gait speed and a higher risk of osteoarthritis," she continued.

The new study examined two biomarkers: circulating levels of vitamin K (phylloquinone) and a functional measure of vitamin K (plasma ucMGP). Using participant data from the Health, Aging, and Body Composition Study (Health ABC), the study found that older adults with low levels of circulating vitamin K were more likely to develop mobility limitation and disability. The other biomarker, plasma ucMGP, did not show clear associations with mobility limitation and disability.

Specifically, older adults with low circulating vitamin K levels were nearly 1.5 times more likely to develop mobility limitation and nearly twice as likely to develop mobility disability compared to those with sufficient levels. This was true for both men and women.

"The connection we saw with low levels of circulating vitamin K further supports vitamin K's association with mobility disability," said senior author Sarah Booth, a vitamin K and nutrition researcher, and director of the HNRCA. "Although the two biomarkers we looked at are known to reflect vitamin K status, biomarker levels can also be affected by additional known or unknown factors. Further experiments to understand the mechanisms of biomarkers and vitamin K and their role in mobility are needed."

The study used data from 635 men and 688 women ages 70-79 years old, approximately 40 percent of whom were black, who participated in Health ABC. In Health ABC, mobility was assessed every six months for six to ten years through annual clinic visits and phone interviews in the intervening time. For the present analysis, the researchers defined mobility limitation as two consecutive semi-annual reports of having any amount of difficulty either with walking a quarter of a mile or climbing 10 steps without resting, and mobility disability as two consecutive semi-annual reports of having a lot of difficulty or inability to walk or climb the same amount.

Circulating vitamin K levels reflect the amount of vitamin K in the diet. The best food sources of vitamin K include leafy greens such as spinach, kale and broccoli and some dairy products. For an average adult, one cup of raw spinach provides 145 micrograms (mcg) of vitamin K1, or 181 percent of the Daily Value; one cup of raw kale provides 113 mcg, or 141 percent; and half of a cup of chopped boiled broccoli provides 110 mcg, or 138 percent.

Madrid, Spain, 13 June 2019: The results of a study presented today at the Annual European Congress of Rheumatology (EULAR 2019) finds the risk of bone mineral density (BMD) loss after denosumab discontinuation is associated with younger age, high bone turnover markers, and not receiving the bisphosphonate, zoledronate, prior to initiation of denosumab.1

The study followed 71 post-menopausal women who were classified into 'loser' or 'stable' groups based on their BMD loss one year after discontinuation of denosumab. Between group analysis revealed that, at initiation of denosumab, the 'loser' group was significantly younger (61.4 ¬+¬7.3 vs. 65.5¬+8.2, p=0.034), with higher level of the bone turnover marker sCTX (644.7 vs. 474.1ng/ml, p=0.005). The use of bisphosphonates after denosumab discontinuation was comparable between groups; however, interestingly none of the 'loser' group had received zoledronate prior to initiation of denosumab vs. 12% of the 'stable' group (p=0.047). Other pre-denosumab characteristics were not different.1

"Our study suggests that being younger, having higher bone turnover markers and not having received zoledronate before denosumab introduction increase the risk of bone mineral density loss following discontinuation of denosumab," said Dr Bérengère Aubry-Rozier, Rheumatology Unit, Lausanne University Hospital, Lausanne, Switzerland. "Our results support the use of denosumab after a bisphosphonate to reduce the bone mineral density loss at its discontinuation, and close monitoring of sCTX to maintain levels below the upper limit of the normal range for premenopausal women."

Denosumab is a human monoclonal antibody that prevents the maturation of osteoclasts by binding to and inhibiting NF-κB ligand (RANKL), a central regulator of bone metabolism. Bisphosphonates, such as zoledronate, act mainly by inhibiting osteoclast-mediated bone resorption and are characterised by their high affinity with bone and a long half-life within the skeleton. This long-lasting retention on bone provides a residual treatment effect on bone resorption even after treatment discontinuation. In contrast, the effect of denosumab is limited to the period of drug exposure. In addition, the discontinuation of denosumab is associated with significant bone turnover rebound, rapid loss of bone mass, and a risk of multiple vertebral fractures.2,3 One to ten per cent of patients are at risk of multiple vertebral fractures, with a median of five vertebral fractures in the seven to 20 months following denosumab discontinuation.3

"There has previously been a lack of evidence related to the risk of fracture following discontinuation of denosumab and measures to prevent it," said Professor Hans Bijlsma, President, EULAR. "Therefore, we welcome these data that will contribute to our understanding in this area."

The study included 71 post-menopausal women from the ReoLaus (Rebound Effect Observatory in Lausanne) Bone Project who had BMD follow up for more than one year after discontinuation of denosumab. Patients who had a lumbar spine BMD loss of over 3.96% at one year after denosumab discontinuation were defined as 'losers' (n=30) with the rest termed 'stable' (n=41).1

Abstract number: OP0085

BOSTON -- (EUREKALERT!) -- Alexion Pharmaceuticals, Inc. today announced the first conference presentation of the topline Phase 3 data for ULTOMIRIS® (ravulizumab), the first and only long-acting C5 complement inhibitor administered every eight weeks, in adult patients with atypical hemolytic syndrome (aHUS). The previously announced data will be presented at the Annual Congress of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), taking place June 13-16, 2019 in Budapest, Hungary:

Efficacy and safety of the long-acting complement C5 inhibitor ravulizumab in adult patients with atypical hemolytic uremic syndrome - Symposium 38, Regular Presentation, June 16, 2019, 09:30 a.m.1

Atypical HUS is a severe and chronic ultra-rare disease that affects both adults and children and can cause progressive and irreversible damage to vital organs, predominantly the kidneys, and lead to kidney failure (requiring dialysis or transplant) and premature death. The disease is characterized by inflammation and blood clotting in small blood vessels throughout the body, called thrombotic microangiopathy (TMA). This inflammation and blood clotting is mediated by chronic, uncontrolled activation of the complement system, which is part of the body's immune system.2,3,4,5,6

Early and careful diagnosis of aHUS is critical as many coexisting diseases and events are known or suspected to activate the complement cascade, and as patients may not necessarily present with the classic TMA triad of thrombocytopenia, hemolytic anemia and renal impairment,7 or may have less severe renal involvement.8 Available tests can help distinguish aHUS from other hemolytic diseases with similar symptoms such as HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS) and thrombotic thrombocytopenic purpura (TTP).6

Alexion submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for the approval of ULTOMIRIS in TMA, including aHUS, in April 2019 and plans to submit similar applications to the European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA) in Japan later this year.

Philadelphia, June 13, 2019 - Antimalarial drugs appear to follow a typical pattern, with early effectiveness eventually limited by the emergence of drug resistance. A report in the Journal of Molecular Diagnostics, published by Elsevier, describes a new assay using whole blood that simplifies the genetic analysis of malarial parasites by completely eliminating processing steps. This provides rapid access to critical information associated with resistance to antimalarials at the point of care, avoiding the time, expense, and effort of having the sample sent to a central laboratory and allowing clinicians to quickly re-evaluate treatment options.

Blood contains a wealth of genetic information, but currently must undergo significant processing to remove components that interfere with molecular analyses. Although an exciting prospect, gathering genetic information from a single drop of blood has proved elusive. This study, which analyzed a single mutation in a malaria parasite, provides the first steps to do just that: a drop of blood can be used directly, without any additional processing, to assess a range of genetic data.

"Monitoring of antimalarial resistance is important to prevent its further spread, but the available options for assessing resistance are less than ideal for field settings. Although molecular detection is perhaps the most efficient method, it is also the most complex because it requires DNA extraction and PCR instrumentation," noted co-lead investigator Mindy Leelawong, PhD, Research Assistant Professor of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. "Our strategy eliminates the most time- and labor-intensive step: DNA extraction. By creating a procedure that overcomes the obstacles presented by blood, we have developed a simple method to quickly identify mutations associated with drug resistance. As a consequence, higher throughput testing and more rapid sample-to-result turnaround will be possible."

"To mitigate the inhibition by blood components, we redesigned the molecular tools used for DNA analysis. We utilized reporter dyes that are more optically compatible with blood, which were combined with a specific type of DNA subunit to accurately pinpoint mutations. The end result is an assay in which blood is directly added to a reaction tube to detect mutations associated with antimalarial drug resistance," explained co-lead investigator Frederick R. Haselton, PhD, of the Departments of Biomedical Engineering and Chemistry at Vanderbilt University.

Dr. Leelawong and Dr. Haselton, along with co-lead investigator David W. Wright, PhD, of the Department of Chemistry at Vanderbilt, anticipate that the technique can be modified for assessing resistance to artemisinin, the current first-line therapy for malarial infection, or future drugs as they become available. The technique may also become a platform for evaluating other molecular targets found in blood.

The technology detailed in this study offers a potential platform to manage the spread of drug resistance on the ground. According to Dr. Wright, "These drug-resistant parasites must not spread; we know from previous generations of drugs that the consequences can be catastrophic. To prevent further spread, the geographic location of drug-resistant parasites must be known."

Malaria is a serious, sometimes fatal disease caused by a parasite that commonly infects a certain type of mosquito that feeds on humans and infects red blood cells. People who contract malaria typically become very sick with high fevers, shaking chills, and flu-like illness. According to the World Malaria Report 2018, there were 219 million cases of malaria globally in 2017 resulting in 435,000 malaria deaths. Although antimalarial drugs are often effective, outcomes are worse for those who are drug resistant.

(BOSTON) -- Like airport security barriers that either clear authorized travelers or block unauthorized travelers and their luggage from accessing central operation areas, the blood-brain-barrier (BBB) tightly controls the transport of essential nutrients and energy metabolites into the brain and staves off unwanted substances circulating in the blood stream. Importantly, it's highly organized structure of thin blood vessels and supporting cells is also the major obstacle preventing life-saving drugs from reaching the brain in order to effectively treat cancer, neurodegeneration, and other diseases of the central nervous system. In a number of brain diseases, the BBB can also locally break down, causing neurotoxic substances, blood cells and pathogens to leak into the brain and wreak irreparable havoc.

To study the BBB and drug-transport across it, researchers have mostly relied on animal models such as mice. However, the precise make-up and transport functions of BBBs in those models can significantly differ from those in human patients, which makes them unreliable for the prediction of drug delivery and therapeutic efficacies. Also in vitro models attempting to recreate the human BBB using primary brain tissue-derived cells thus far have not been able to mimic the BBB's physical barrier, transport functions, and drug and antibody shuttling activities closely enough to be useful as therapeutic development tools.

Now, a team led by Donald Ingber, M.D.,Ph.D. at Harvard's Wyss Institute for Biologically Inspired Engineering has overcome these limitations by leveraging its microfluidic Organs-on-Chips (Organ Chips) technology in combination with a developmentally-inspired hypoxia-mimicking approach to differentiate human pluripotent stem (iPS) cells into brain microvascular endothelial cells (BMVECs). The resulting 'hypoxia-enhanced BBB Chip' recapitulates cellular organization, tight barrier functions and transport abilities of the human BBB; and it allows the transport of drugs and therapeutic antibodies in a way that more closely mimics transport across the BBB in vivo than existing in vitro systems. Their study is reported in Nature Communications.

"Our approach to modeling drug and antibody shuttling across the human BBB in vitro with such high and unprecedented fidelity presents a significant advance over existing capabilities in this enormously challenging research area," said Wyss Institute Founding Director Ingber. "It addresses a critical need in drug development programs throughout the pharma and biotech world that we now aim to help overcome with a dedicated 'Blood-Brain Barrier Transport Program' at the Wyss Institute using our unique talent and resources." Ingber is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children's Hospital, as well as Professor of Bioengineering at SEAS.

The BBB consists of thin capillary blood vessels formed by BMVECs, multifunctional cells known as pericytes that wrap themselves around the outside of the vessels, and star-shaped astrocytes, which are non-neuronal brain cells that also contact blood vessels with foot-like processes. In the presence of pericytes and astrocytes, endothelial cells can generate the tightly sealed vessel wall barrier typical of the human BBB.

Ingber's team first differentiated human iPS cells to brain endothelial cells in the culture dish using a method that had been previously developed by co-author Eric Shusta, Ph.D., Professor of Chemical and Biological Engineering at University of Wisconsin-Madison, but with the added power of bioinspiration. "Because in the embryo, the BBB forms under low-oxygen conditions (hypoxia), we differentiated iPS cells for an extended time in an atmosphere with only 5% instead of the normal 20% oxygen concentration," said co-first author Tae-Eun Park, Ph.D. "As a result, the iPS cells initiated a developmental program very similar to that in the embryo, producing BMVECs that exhibited higher functionality than BMVECs generated in normal oxygen conditions." Park was a Postdoctoral Fellow on Ingber's team and now is Assistant Professor at Ulsan National Institute of Science and Technology in the Republic of Korea.

Building on a previous human BBB model, the researchers next transferred the hypoxia-induced human BMVECs into one of two parallel channels of a microfluidic Organ-on-Chip device that are divided by a porous membrane and continuously perfused with medium. The other channel was populated with a mixture of primary human brain pericytes and astrocytes. Following an additional day of hypoxia treatment, the human BBB chip could be stably maintained for at least 14 days at normal oxygen concentrations, which is far longer than past in vitro human BBB models attempted in the past.

Under the shear stress of the fluids perfusing the BBB Chip, the BMVECs go on to form a blood vessel, and develop a dense interface with pericytes aligning with them on the other side of the porous membrane, as well as with astrocytes extending processes towards them through small openings in the membrane. "The distinct morphology of the engineered BBB is paralleled by the formation of a tighter barrier containing elevated numbers of selective transport and drug shuttle systems compared to control BBBs that we generated without hypoxia or fluid shear stress, or with endothelium derived from adult brain instead of iPS cells," said Nur Mustafaoglu, Ph.D., a co-first author on the study and Postdoctoral Fellow working on Ingber's team. "Moreover, we could emulate effects of treatment strategies in patients in the clinic. For example, we reversibly opened the BBB for a short time by increasing the concentration of a mannitol solute [osmolarity] to allow the passage of large drugs like the anti-cancer antibody Cetuximab."

To provide additional proof that the hypoxia-enhanced human BBB Chip can be utilized as an effective tool for studying drug delivery to the brain, the team investigated a series of transport mechanisms that either prevent drugs from reaching their targets in the brain by pumping them back into the blood stream (efflux), or that, in contrast, allow the selective transport of nutrients and drugs across the BBB (transcytosis).

"When we specifically blocked the function of P-gp, a key endothelial efflux pump, we could substantially increase the transport of the anti-cancer drug doxorubicin from the vascular channel to the brain channel, very similarly to what has been observed in human patients," said Park. "Thus, our in vitro system could be used to identify new approaches to reduce efflux and thus facilitate drug transport into the brain in the future."

On another venue, drug developers are trying to harness 'receptor-mediated transcytosis' as a vehicle for shuttling drug-loaded nanoparticles, larger chemical and protein drugs, as well as therapeutic antibodies across the BBB. "The hypoxia-enhanced human BBB Chip recapitulates the function of critical transcytosis pathways, such as those used by the LRP-1 and transferrin receptors responsible for taking up vital lipoproteins and iron from circulating blood and releasing them into the brain on the other side of the BBB. By harnessing those receptors using different preclinical strategies, we can faithfully mimic the previously demonstrated shuttling of therapeutic antibodies that target transferrin receptors in vivo, while maintaining the BBB's integrity in vitro," said Mustafaoglu.

Based on these findings, the Wyss Institute has initiated a 'Blood-Brain Barrier Transport Program'. "Initially, the BBB Transport Program aims to discover new shuttle targets that are enriched on the BMVEC vascular surface, using novel transcriptomics, proteomics, and iPS cell approaches. In parallel, we are developing fully human antibody shuttles directed against known shuttle targets with enhanced brain-targeting capabilities," said James Gorman, M.D., Ph.D., the Staff Lead for the BBB Transport Program working with Ingber. "We aim to collaborate with multiple biopharmaceutical partners in a pre-competitive relationship to develop shuttles offering exceptional efficacy and engineering flexibility for incorporation into antibody and protein drugs, because this is so badly needed by patients and the whole field".

The authors think that in addition to drug development studies, the hypoxia-enhanced human BBB Chip can also be used to model aspects of brain diseases that affect the BBB such as Alzheimer's and Parkinson's disease, and to advanced personalized medicine approaches by using patient-derived iPS cells.